Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

Abstract

PURPOSE:

A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity.

PATIENTS AND METHODS:

A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD.

RESULTS:

Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition.

CONCLUSION:

The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

• Authors: A M Langevin, D T Casto, P J Thomas, S D Weitman, C Kretschmar, H Grier, C Pratt, R Dubowy, M Bernstein, S Blaney, T Vietti
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 16 Issue 7 Pg. 2494-9 (Jul 1998) ISSN: 0732-183X [Print] United States
• PMID: 9667269 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• 9-aminocamptothecin
• Camptothecin

Topics

• Adolescent
• Adult
• Antineoplastic Agents (administration & dosage, adverse effects, blood, pharmacokinetics)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives, blood, pharmacokinetics)
• Child
• Child, Preschool
• Drug Administration Schedule
• Female
• Humans
• Male
• Maximum Allowable Concentration
• Neoplasms (blood, drug therapy)
• Treatment Outcome
• United States